Brain astrocyte urea cycle controls memory loss in Alzheimer’s disease-ScienceDaily

Researchers led by C. Justin LEE, director of the Center for Cognition and Sociality within the Korea Institute for Fundamental Sciences (IBS), have delved into this topic extensively.Recently in 2020, the group was published in a journal Nature Neuroscience Star-shaped cells in the brain called astrocytes are significantly involved in Alzheimer’s disease and its progression. Driven by this discovery, the group sought to further explore the molecular connections that underlie the reactions of astrocytes.

After studying the basic cellular pathways and how they change in the astrocytes of the brain, the IBS team discovered the missing link of amyloid beta-to-urea conversion in the brain. did.

The urea cycle is widely studied and understood as the major metabolic pathway of the liver and kidney as part of our digestive and excretory process. In the liver, the urea cycle converts ammonia, a toxic product from protein digestion, into urea. Urea is easily excreted from the kidneys as urine. Surprisingly, previous studies reported an increase in urea in the brains of patients with Alzheimer’s disease, and the IBS team wondered if the urea cycle played a role in the pathology of the disease. Surprisingly, they found that the urea cycle was “switched on” in the astrocytes of the Alzheimer’s disease brain to purify toxic amyloid beta aggregates and remove them in the form of urea. discovered.

However, this is not as beneficial as you might think. The group discovered that when the urea cycle was switched on, another metabolite that accumulates inside the cell, ornithine, was produced and needed to be cleaned up. Hard-working astrocytes produce the enzyme ornithine decarboxylase 1 (ODC1) in this state, processing the accumulated ornithine and converting it to putrescine. As a result, the neurotransmitter γ-aminobutyric acid (GABA), and hydrogen peroxide (H)₂O₂) And ammonia in the brain.

This ammonia is further fed back into the urea cycle, continuing this process and increasing the accumulation of toxic by-products. High levels of GABA released by these astrocytes act to inhibit neurotransmission and contribute to memory loss in Alzheimer’s disease.

The above 2020 study by the group found that hydrogen peroxide causes severe reactivity in astrocytes and is a major factor in neuronal cell death.Now, the new findings from this study explain exactly how the increase in GABA, H increased.₂O_2, Ammonia contributes to and exacerbates the memory loss and neuronal cell death associated with Alzheimer’s disease.

Lead author JU Yeon Ha said, “Scientists have been discussing the beneficial and detrimental role of reactive astrocytes for years. The results of this study have brought our group to a beneficial urea circuit. The conversion of ornithine to putresin and GABA provides evidence of the dual nature of astrocytes in the Alzheimer’s disease brain. “

The group conducted further experiments to take advantage of this new knowledge. They found that stellate cell-specific gene silencing of the enzyme ornithine decarboxylase 1 in a mouse model of transgenic Alzheimer’s disease could block excessive GABA production and neuronal suppression in the hippocampus of the mouse brain. These animals functioned better in memory-related behavioral tasks and almost completely recovered from AD-related memory loss after ODC1 knockdown.In addition, the number of amyloid beta plaques is significantly lower in the brains of mice silencing the ODC1 gene, and the urea cycle works more efficiently to remove accumulated proteins without causing the accumulation of harmful by-products such as H. Shows that you did₂O₂GABA and ammonia.

The corresponding author of the study, director C. Justinley, said: “The results of this study were able to finally depict the pathways that link amyloid beta plaque to astrocyte reactivity and reveal the existence of a functional urea cycle in reactive astrocytes. We also found elevated levels of the enzyme ODC1 in the brains of human AD patients, which increases the likelihood of converting the results of mouse studies to humans, making ODC1 a novel and powerful treatment for the disease. It has been shown to be a target, which may not only remove amyloid beta plaques, but also improve memory. “

This study was published in Cell metabolism, A Cell Press journal with a strong impact factor of 27.28. Due to the importance and novelty of the research, the lead author, Dr. JU Yeonha, was invited to present the findings at the journal symposium. Signal transduction and metabolites in disease In April in Lisbon, Portugal.